Empagliflozin reduced the combined relative risk of cardiovascular death and hospitalization for heart failure by 25 per cent in adults with and without diabetes who had heart failure with reduced ejection fraction

Burlington, ON and Toronto, ON – September 8, 2020 – Full results from the EMPEROR-Reduced Phase III trial in adults with heart failure with reduced ejection fraction, with and without diabetes, showed that empagliflozin was associated with a significant 25 per cent relative risk reduction in the primary endpoint of time to cardiovascular death or hospitalization due to heart failure.¹ The trial evaluated the effect of adding empagliflozin (10 mg) versus placebo to standard of care.¹ The results were presented on August 29^th at the ESC Congress 2020, the annual meeting of the European Society of Cardiology,³ and published in The New England Journal of Medicine,¹ Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced.

The findings from the primary endpoint were consistent in subgroups with and without type 2 diabetes.¹ Key secondary endpoint analyses from the trial demonstrated that empagliflozin reduced the relative risk of first and recurrent hospitalization for heart failure by 30 per cent.¹ Additionally, the rate of decline in eGFR, a measure of kidney function decline, was slower with empagliflozin than with placebo.¹

"Heart failure is a devastating disease affecting hundreds of thousands of Canadians. Unfortunately the condition becomes progressively worse over time, leading to long and frequent hospitalizations paired with additional complications such as kidney disease,” said Dr. Subodh Verma, a Professor and Cardiac Surgeon at the University of Toronto at St Michael’s Hospital, who served as the Canadian lead investigator for the trial and as a member of the Scientific Excellence Committee for the EMPEROR Program. “Results from the EMPEROR-Reduced trial show that empagliflozin reduced the number of hospitalizations due to heart failure while slowing the rate of decline in kidney function when given to adults with heart failure with reduced ejection fraction. These data position empagliflozin as a new therapy in the treatment of heart failure.”

In an exploratory analysis, the absolute risk reduction observed in the primary endpoint of EMPEROR-Reduced corresponded to a number needed to treat of 19 patients over 16 months to prevent one cardiovascular death or hospitalization for heart failure.¹ An additional exploratory analysis showed that empagliflozin decreased the relative risk of a composite kidney endpoint*, including end stage kidney disease and a profound loss of kidney function, by 50 per cent.¹

“Heart failure can have a profound impact on people living with the condition, with the potential of life limiting consequences for the heart and the kidneys,” said Waheed Jamal, M.D., Corporate Vice President and Head of CardioMetabolic Medicine, Boehringer Ingelheim. "Empagliflozin was the first SGLT2 inhibitor to demonstrate a reduction in cardiovascular death and hospitalization due to heart failure in people with type 2 diabetes and established cardiovascular disease, based on the EMPA-REG OUTCOME^® trial. We continue to break new ground with the EMPEROR-Reduced results, which provide robust evidence that empagliflozin can transform the lives of millions of people through reducing cardiovascular outcomes and slowing the progression of kidney damage in people with heart failure. We look forward to exploring these data further and are planning regulatory submissions for later this year.”

“Tens of millions of people live with heart failure and kidney disease,” said Jeff Emmick, M.D., Ph.D., Vice President, Product Development, Lilly. “Results from EMPEROR-Reduced show that empagliflozin can help improve heart failure outcomes while also slowing kidney function decline. We are excited to share these data and, through our ongoing EMPOWER program, hope to redefine how people living with these conditions are treated.”

In EMPEROR-Reduced, the efficacy results were achieved with a simple dosing regimen, with once daily dosing and no need for titration.1 The safety profile was similar to the well-established safety profile of empagliflozin.¹ There were no clinically meaningful differences in adverse events including hypovolemia (decreased blood volume), hypotension (low blood pressure), volume depletion (loss of fluids), renal insufficiency (poor kidney function), hyperkalemia (high potassium levels) or hypoglycemic events (low blood sugar) compared with placebo.¹

Heart failure affects over 60 million people worldwide,⁴ with an estimated 600,000 Canadians currently living with heart failure.² Heart failure occurs when the heart cannot pump sufficient blood to the rest of the body and is the most common and severe complication of a heart attack.^2,5 People with heart failure often experience breathlessness and fatigue, which can severely impact their quality of life.^2,6 Individuals with heart failure often also have impaired kidney function, which can have a significant negative impact on prognosis.⁷

 “As a heart failure survivor and patient advocate, I live and see the effects of heart failure on a daily basis,” said Marc Bains Co-Founder of HeartLife Foundation. “Through working with patients across Canada I know innovation in the area of heart failure treatment gives hope to patients that they can protect their quality of life, and continue to share meaningful moments with their loved ones.”

* Composite exploratory endpoint included chronic dialysis or renal transplant or sustained reduction of ≥ 40 per cent in eGFR (CKD-EPI) or a sustained eGFR < 15 mL/min/1.73m² (for patients with baseline eGFR ≥ 30) or sustained eGFR < 10 mL/min/1.73m² (for patients with baseline eGFR < 30 mL/min/1.73m²).

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About the EMPEROR Heart Failure Studies^8,9
The EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) heart failure studies are two Phase III, randomized, double-blind trials investigating once-daily empagliflozin compared with placebo in adults with heart failure with preserved or reduced ejection fraction**, both with and without diabetes, who are receiving current standard of care:

• EMPEROR-Reduced [NCT03057977] investigated the safety and efficacy of empagliflozin in patients with chronic heart failure with reduced ejection fraction (HFrEF).
  • Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure
  • Number of patients: 3,730; which included 36 study sites in Canada
  • Completion: 2020
• EMPEROR-Preserved [NCT03057951] investigates the safety and efficacy of empagliflozin in patients with chronic heart failure with preserved ejection fraction (HFpEF).
  • Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure [Time Frame: up to 38 months]
  • Anticipated number of patients: approx. 5,990
  • Estimated completion: 2021

** Ejection fraction is a measurement of the percentage of blood the left ventricle pumps out with each contraction.¹⁰ When the heart relaxes, the ventricle refills with blood.

• HFrEF occurs when the heart muscle does not contract effectively, and less blood is pumped out to the body compared with a normally functioning heart.¹⁰
• HFpEF occurs when the heart muscle contracts normally but the ventricle does not fill with enough blood, so less blood can enter the heart compared with a normally functioning heart.¹⁰

About the EMPOWER program
The Alliance has developed the EMPOWER program to explore the impact of empagliflozin on major clinical cardiovascular and renal outcomes in a spectrum of cardio-renal-metabolic conditions. Cardio-renal-metabolic conditions are the leading cause of mortality worldwide and account for up to 20 million deaths annually.¹¹ Through the EMPOWER program, Boehringer Ingelheim and Lilly are working to advance knowledge of these interconnected systems and create care which offers integrated, multi-organ benefits. Comprised of eight clinical trials and two real-world evidence studies, EMPOWER reinforces the long-term commitment of the Alliance to improve outcomes for people living with cardio-renal-metabolic conditions. With more than 257,000 adults studied worldwide in clinical studies, it is the broadest and most comprehensive clinical program for an SGLT2 inhibitor to date. 

The development program encompasses:

• EMPEROR-Reduced, in adults with chronic heart failure with reduced ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure¹
• EMPEROR-Preserved, in adults with chronic heart failure with preserved ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure⁸
• EMPULSE, in adults hospitalized for acute heart failure to improve clinical and patient reported outcomes¹²
• EMPACT-MI, to evaluate all-cause mortality and hospitalization for heart failure in adults with and without type 2 diabetes who have had an acute myocardial infarction, with the aim to prevent heart failure and improve outcomes¹³
• EMPA-KIDNEY, in adults with established chronic kidney disease to reduce the progression of kidney disease and the occurrence of cardiovascular death¹³
• EMPERIAL-Reduced, in adults with chronic heart failure with reduced ejection fraction to evaluate functional ability and patient reported outcomes¹⁴
• EMPERIAL-Preserved, in adults with chronic heart failure with preserved ejection fraction to evaluate functional ability and patient-reported outcomes¹⁵
• EMPA-REG OUTCOME, in adults with type 2 diabetes and established cardiovascular disease to prevent major adverse cardiovascular events, including cardiovascular death¹⁶
• EMPRISE, a non-interventional study of the effectiveness, safety, healthcare utilization and cost of care of empagliflozin in routine clinical practice in adults with type 2 diabetes across the cardiovascular risk continuum^17,18

About Heart Failure
Heart failure is a progressive, debilitating and potentially fatal condition that occurs when the heart cannot supply adequate circulation to meet the body’s demands for oxygenated blood or to do so requires increased blood volume leading to fluid accumulation (congestion) in the lungs and peripheral tissues.² An estimated 600,000 Canadians are living with heart failure.² Worldwide 60 million people are affected and the prevalence is expected to increase as the population ages.⁴ Heart failure is highly prevalent in people with diabetes;¹⁹ however, approximately half of all people with heart failure do not have diabetes.^4,20

The empagliflozin heart failure program was initiated based on data from the EMPA-REG OUTCOME trial, which assessed the effect of empagliflozin (10 mg or 25 mg once daily) in adults with type 2 diabetes and established cardiovascular disease when added to standard of care, compared with placebo.¹⁷

About Cardio-Renal-Metabolic Conditions
Boehringer Ingelheim and Lilly are driven to transform care for people with cardio-renal-metabolic conditions, a group of interconnected disorders that affect more than one billion people worldwide and are a leading cause of death.²¹

The cardiovascular, renal and metabolic systems are interconnected, and share many of the same risk factors and pathological pathways along the disease continuum. Dysfunction in one system may accelerate the onset of others, resulting in progression of interconnected diseases such as type 2 diabetes, cardiovascular disease, heart failure, and kidney disease, which in turn leads to an increased risk of cardiovascular death. Conversely, improving the health of one system can lead to positive effects throughout the others.^22,23

Through our research and treatments, our goal is to support people’s health, restoring the balance between the interconnected cardio-renal-metabolic systems and reducing their risk of serious complications. As part of our commitment to those whose health is jeopardized by cardio-renal-metabolic conditions, we will continue embracing a multidisciplinary approach towards care and focusing our resources on filling treatment gaps.

About Empagliflozin
Empagliflozin is an oral, once daily, highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor and the first type 2 diabetes medicine to include cardiovascular death risk reduction data in its label in several countries.^24,25

Inhibition of SGLT2 with empagliflozin in people with type 2 diabetes and high blood sugar levels prevents sugar being re-absorbed by the kidneys, leading to the excretion of excess sugar in the urine. In addition, initiation of empagliflozin also prevents salt being re-absorbed, leading to increased excretion of salt from the body and reducing the fluid load of the body’s blood vessel system (i.e. intravascular volume). Empagliflozin induces changes to the sugar, salt and water metabolism in the body that may contribute to the reductions in cardiovascular death observed in the EMPA-REG OUTCOME trial.²⁶

About Boehringer Ingelheim and Eli Lilly and Company
In January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an alliance in the field of diabetes that centres on three pipeline compounds representing several of the largest treatment classes. This Alliance leverages the strengths of two of the world's leading pharmaceutical companies, combining Boehringer Ingelheim's solid track record of research-driven innovation and Lilly's innovative research, experience and pioneering history in diabetes. By joining forces, the companies demonstrate commitment in the care of people with diabetes and stand together to focus on patient needs. For more information about the Alliance visit www.boehringer-ingelheim.ca or www.lilly.ca.

About Boehringer Ingelheim (Canada) Ltd.
Making new and better medicines for humans and animals is at the heart of what we do. Our mission is to create innovative therapies that change lives. Since its founding in 1885, Boehringer Ingelheim is independent and family-owned. We have the freedom to pursue our long-term vision, looking ahead to identify the health challenges of the future and targeting those areas of need where we can do the most good.

As a world-leading, research-driven pharmaceutical company, more than 51,000 employees create value through innovation daily for our three business areas: Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. In 2019, Boehringer Ingelheim achieved net sales of 19 billion euros. Our significant investment of almost 3.5 billion euros in R&D drives innovation, enabling the next generation of medicines that save lives and improve quality of life.

We realize more scientific opportunities by embracing the power of partnership and diversity of experts across the life-science community. By working together, we accelerate the delivery of the next medical treatment that will transform the lives of patients now, and in generations to come.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Montreal, Quebec and is now located in Burlington, Ontario. Boehringer Ingelheim employs approximately 600 people across Canada.

More information about Boehringer Ingelheim can be found at www.boehringer-ingelheim.ca or in our annual report: http://annualreport.boehringer-ingelheim.com.

About Eli Lilly Canada
Eli Lilly and Company is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by Colonel Eli Lilly, who was committed to creating high quality medicines that meet people’s needs, and today we remain true to that mission in all our work. Lilly employees work to discover and bring life-changing medicines to people who need them, improve the understanding and management of disease, and contribute to our communities through philanthropy and volunteerism.

Eli Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto, which eventually produced the world’s first commercially-available insulin. Our work focuses on oncology, diabetes, autoimmunity, neurodegeneration, and pain. To learn more about Lilly Canada, please visit us at www.lilly.ca.

For our perspective on issues in healthcare and innovation, follow us on twitter @LillyPadCA.

CONTACTS:

Anne Coffey
Specialist, Brand Communications
Boehringer Ingelheim (Canada) Ltd.
Email: anne.coffey@boehringer-ingelheim.com
Phone: (416) 526-5388

Helen Stone
Manager, Communications
Eli Lilly Canada Inc.
Email: stone_helen@lilly.com
Phone: (416) 693-3169

References

1. Packer M, Anker SD, Butler J, et al. Cardiac and Renal Outcomes With Empagliflozin in Heart Failure With a Reduced Ejection Fraction. N Engl J Med. 2020;10.1056/NEJMoa2022190
2. Heart and Stroke Foundation of Canada. Heart failure. Available at: https://www.heartandstroke.ca/heart/conditions/heart-failure. Accessed July 2020.
3. Packer M. EMPEROR-Reduced: Empagliflozin in Heart Failure With a Reduced Ejection Fraction, With and Without Diabetes. Presented on 29 August 2020 at the European Society of Cardiology (ESC) Congress 2020 – The Digital Experience.
4. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–1858.
5. Anderson JL and Morrow DA. Acute Myocardial Infarction. N Engl J Med. 2017;376:2053–64.
6. Calvert MJ, Freemantle N, Cleland JGF. The impact of chronic heart failure on health‐related quality of life data acquired in the baseline phase of the CARE‐HF study. Eur J Heart Fail. 2005;7(2):243–51.
7. Sarnak MJ. A patient with heart failure and worsening kidney function. Clin J Am Soc Nephrol. 2014;9(10):1790–98.
8. ClinicalTrials.gov. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). Available at: https://clinicaltrials.gov/ct2/show/NCT03057951. Accessed August 2020.
9. ClinicalTrials.gov. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced). Available at: https://clinicaltrials.gov/ct2/show/NCT03057977. Accessed August 2020.
10. American Heart Association. Ejection Fraction Heart Failure Measurement. Available at: https://www.heart.org/en/health-topics/heart-failure/diagnosing-heart-failure/ejection-fraction-heart-failure-measurement. Accessed: August 2020.
11. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016; 388(10053):1459–544.
12. ClinicalTrials.gov. EMPagliflozin initiated in patients hospitalised for acUte heart faiLure (de novo or decompensated chronic HF) who have been StabilisEd (EMPULSE) Available at: https://www.clinicaltrials.gov/ct2/show/NCT04157751. Accessed August 2020.
13. ClinicalTrials.gov. EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin). Available at: https://clinicaltrials.gov/ct2/show/NCT03594110. Accessed August 2020.
14. ClinicalTrials.gov. A phase III randomised, double-blind trial to evaluate the effect of 12 weeks treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart failure symptoms, In patients with chronic HeArt FaiLure with reduced Ejection Fraction (HFrEF) (EMPERIAL – reduced). Available at: https://clinicaltrials.gov/ct2/show/NCT03448419. Accessed August 2020.
15. ClinicalTrials.gov. A phase III randomised, double-blind trial to evaluate the effect of 12 weeks treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart failure symptoms, in patients with chronic HeArt FaiLure with preserved Ejection Fraction (HFpEF) (EMPERIAL – preserved). Available at: https://clinicaltrials.gov/ct2/show/NCT03448406. Accessed August 2020.
16. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117–28.
17. Kim DJ, Sheu WH-H, Seino Y, et al. Cardiovascular Effectiveness and Safety of Empagliflozin in Routine Care in East Asia: Results from the EMPRISE study. Presented at IDF Congress 2019. 2-6 December 2019, Busan, Korea.
18. Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) Trial. Circulation. 2019;139:2822-30.
19. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;128(16):e240–e327.
20. Suskin N, McKelvie RS, Burns RJ, et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J. 2000;21:1368–75.
21. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016; 388(10053):1459–544.
22. Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010;31(6):703–11.
23. Lazzeri C, Valente S, Tarquini R, et al. Cardiorenal syndrome caused by heart failure with preserved ejection fraction. Int J Nephrol. 2011;2011:634903.
24. Product Monograph Jardiance®. Canada. Available at: https://www.boehringer-ingelheim.ca/sites/ca/files/documents/jardiancepmen.pdf. Accessed: August 2020.
25. Jardiance® (empagliflozin) tablets. European Product Information; approved April 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf. Accessed August 2020.
26. Vallon V and Thompson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25.